The present invention relates generally to the observation of a correlation between the production of bioactive IL-1β by bone marrow cells and the clinical features of multiple myeloma.
Despite aggressive treatment approaches, multiple myeloma (MM) is a universally fatal B cell malignancy, accounting for 1-2% of all cancer deaths. See Silverberg et al. (1996) Ca. J. Clin. 46: 5-27. MM is recognized clinically by the proliferation of malignant plasma cells in the bone marrow, the detection of a monoclonal protein (M protein) in the serum or urine, anemia, hypercalcemia, renal insufficiency and lytic bone lesions. See Kyle and Lust (1989) Seminars in Hematology 26: 176-200. Several multiple myeloma-related plasmaproliferative disorders, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), are characterized by the detection of M protein in the serum or urine without the other clinical features of MM. MGUS, a clinically benign precursor condition of MM is more common than MM, occurring in 1% of the population over age 50 and 3% of those over age 70. Greipp and Lust (1995) Stem Cells 13: 10-21. It is of great clinical importance to distinguish patients with MGUS from those with MM, as MGUS patients may be safely observed without resort to chemotherapy. The unnecessary treatment of MGUS patients can lead to acute leukemia or morbidity/mortality from chemotherapy. However, during long-term follow-up, of 241 patients with MGUS, 59 patients (24.5%) went on to develop MM or a related disorder. See Kyle (1993) Mayo Clinic Proceedings 68: 28. Thus, the prevention of myeloma from MGUS would have a significant impact on the morbidity and mortality of myeloma.
Chemotherapy and peripheral blood stem cell transplant are the treatments for symptomatic patients with active MM. Patients who are candidates for peripheral blood stem cell harvest typically receive four cycles of VAD (vincristine, doxorubicin [Adriamycin] and dexamethasone) chemotherapy followed by peripheral blood cell harvest. Subsequently, myeloma patients either continue on standard chemotherapy such as VBMCP (vincristine, carmustine [BCNU], melphalan, cyclophosphamide and prednisone) or proceed directly to transplant. See Attal et al. (1996) N. Engl. J. Med. 335: 91 and Alexanian and Dimopoulos (1994) N. Engl. J. Med. 330: 484. Patients who are not candidates for transplantation receive standard chemotherapy consisting of either VBMCP or melphalan in combination with prednisone. See Oken et al. (1997) Cancer 79: 1561. Recently, thalidomide has been shown to have activity in patients with recurrent myeloma. See Singhal et al. (2000) N. Engl. J. Med. 2000; 342(5): 364 and Singhal et al. (1999) N. Engl. J. Med. 341: 1565. Chemotherapy is usually continued until the patient has reached a plateau state, which is defined as a stable M protein in the serum and urine and no evidence of progression of myeloma. In most patients, chemotherapy plus analgesics can control the bone pain characteristic of the disease. The duration of survival of patients with MM ranges from a few months to many years with the median survival of 2.5-3 years. See Oken et al., supra. Even with transplantation, except for a rare patient, all patients eventually relapse and succumb to their disease. See Attal et al. supra.
Newer therapeutic strategies for MM are clearly needed. The prevention or delay of the progression to MM from related plasmaproliferative disorders, such as MGUS and SMM, with an effective chemotherapeutic agent would have a major impact on the treatment of patients with plasmaproliferative disorders.